A need exists for compounds which inhibit angiotensin converting enzyme (hereinafter ACE). The inhibition of ACE blocks the conversion of the decapeptide angiotensin I to angiotensin II. Angiotensin II is a potent pressor substance, therefore blood pressure lowering can result from inhibition of its biosynthesis, especially in animals and humans whose hypertension is angiotensin II related. Furthermore, ACE inhibition may also lower blood pressure by potentiation of bradykinin. Although the relative importance of these and other possible mechanisms remains to be established, ACE inhibitors are effective antihypertensive agents in a variety of animal models and are useful clinically in treating human patients with renovascular, malignant and essential hypertension. See, e.g., D. W. Cushman, et al., Biochemistry, 16, 5484 (1977).
Additionally, a need exists for compounds which are anti-ischemic agents useful in the treatment of reperfusion injury. Reperfusion injury is that injury which occurs when molecular oxygen is reintroduced into an ischemic tissue. An ischemic tissue is one that is deficient of blood due to a functional constriction or actual obstruction of a blood vessel. Ischemia (i.e., the deficiency of oxygenated blood in a tissue) can be caused by any means and in any tissue and includes ischemia to the heart or a portion of the heart resulting from a coronary thrombosis or any other blockage of the blood supply to the heart or a portion of the heart, ischemia surgically induced to the heart of a patient undergoing open-heart or coronary by-pass surgery, the ischemia which occurs to an organ group such as a heart, heart-lung, liver, or kidney to be used in an organ transplant, ischemia occuring during circulatory shock, and ischemia which is caused by blockage of the arteries supplying the brain, i.e. stroke.
Likewise, a need exists for compounds that exert a strenghtening effect on the heart tissue of patients who have suffered heart failure. Heart failure, or cardiotonia, is the clinical condition resulting from the inability of the myocardium of the ventricles to maintain an adequate flow of blood to all the tissues of the body and includes backward heart-failure, congestive heart-failure, forward heart-failure, and left and right ventricular heart-failure. A cardiotonic agent is an agent which strenghtens the heart's action. The compounds effective in treatment of heart-failure function by strengthening the heart muscle by virtue of their ability to enhance myocardial contractile force and by reducing work load by virtue of their vasodilator activity.